Abstract
Natural killer (NK) cells have received a lot of attention in recent years for the roles they play in immunity and particularly in antitumor immune responses. Although defects in NK cell functions are recognized as important mechanisms for immune evasion of malignant cells, molecular pathways regulating NK cell dysfunction and exhaustion in cancer are largely unknown. Here we tested whether the c-myc proto-oncogene, known to promote cell proliferation, growth, differentiation, and apoptosis by regulating the expression of numerous target genes, may be involved in the mechanism of NK cell abnormalities in patients with lung and gastric cancer. Analysis of c-myc mRNA and protein expression in peripheral blood NK cells, mitogen-activated protein kinase (MAPK) activity, cell cycle, and cell longevity revealed a significantly decreased expression of c-myc mRNA and protein and mitotic arrest of NK cells in different phases of cell cycle. In addition, a significant decrease of NK cell death was also detected. These data allow the suggestion that defects of NK cell-mediated tumor surveillance may be associated with disturbed c-myc expression in NK cells in cancer patients. A better understanding of the mechanisms of NK cell dysfunction in cancer will help in the NK cell-mediated therapeutic eradication of primary and metastatic cancer cells and prolong patient survival.
Highlights
The immune system has a tremendous capacity for defense mechanisms surveilling the appearance, development, and progression of malignant tumors
Our results suggested that altered signaling and expression of c-kit/SCF, c-myc and STAT3 in Natural killer (NK) cells from cancer patients was responsible for the defect in NK cell cytolytic activity seen in many patients and that these abnormalities in the gene expression may be the cause rather than the result of tumor progression
We reported here that c-myc expression in NK cells, on the contrary to cancerous cells, decreased, while the low level of apoptotic death is a similar attribute in tested cells
Summary
The immune system has a tremendous capacity for defense mechanisms surveilling the appearance, development, and progression of malignant tumors. The most important innovative potential of the manuscript is in confirmation and further expansion of unique recent findings of abnormal c-myc expression in NK cells isolated from patients with lung and stomach cancer, but in further development of clinically important data. This includes data validation on both the mRNA and protein levels, analysis of c-myc expression in cells on different stages of cell cycle and cell viability, and, most importantly, evaluation of c-myc expression in NK cells harvested before and after surgical tumor excision. These new data offer a basis for a novel concept of tumor-associated immunosuppression and offer new targets in NK cells for development innovative and efficient cancer therapies
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